Thorough QT/QTc study of tocilizumab after single-dose administration at therapeutic and supratherapeutic doses in healthy subjects. 2011

S Grange, and C Schmitt, and L Banken, and B Kuhn, and X Zhang
Hoffmann-La Roche AG, Basel, Switzerland.

OBJECTIVE The study was intended to determine whether tocilizumab has a threshold pharmacologic effect on cardiac repolarization as detected by QT/QTc prolongation on 12-lead electrocardiograms (ECGs) in healthy subjects. METHODS This was a multicenter, double-blind, placebo- and active-controlled, parallel group study. Healthy subjects received either an intravenous infusion of tocilizumab 10 mg/kg (n = 30) or 20 mg/kg (n = 31), oral moxifloxacin 400 mg (n = 31), or placebo (n = 29). Triplicate ECGs were obtained at predose, 2 h postdose on Day 1, and on Days 8, 15, and 29. Blood samples for pharmacokinetic analyses were collected at predose and up to 28 days postdose. Adverse events and laboratory safety tests were assessed throughout the study. RESULTS Estimated mean study-specific, heart rate-corrected QT interval change from time-matched baseline versus placebo was negative at all time points (range -5.4 to -1.0 ms); the associated upper bound of the 1-sided 95% confidence limit was below threshold (10 ms). No clinically significant abnormalities in other electrocardiographic parameters were detected. No electrocardiographic abnormalities constituted an adverse event. After tocilizumab dosing, median time to maximum serum concentration was 2 h postdose; mean apparent terminal half-life was 9.3 ± 1.2 (10 mg/kg) and 12.1 ± 1.5 (20 mg/kg) days. Tocilizumab was well tolerated. Neutrophil counts decreased after tocilizumab administration, reaching a nadir 2 to 5 days after infusion. Mean neutrophil counts returned to baseline in the 10-mg/kg group and were near baseline in the 20-mg/kg group at the follow-up visit (Day 50 ± 2). CONCLUSIONS There was no QT prolongation effect of clinical concern by tocilizumab at both the therapeutic (10 mg/kg) and the supratherapeutic (20 mg/kg) dose in healthy subjects.

UI MeSH Term Description Entries
D008297 Male Males
D008875 Middle Aged An adult aged 45 - 64 years. Middle Age
D004311 Double-Blind Method A method of studying a drug or procedure in which both the subjects and investigators are kept unaware of who is actually getting which specific treatment. Double-Masked Study,Double-Blind Study,Double-Masked Method,Double Blind Method,Double Blind Study,Double Masked Method,Double Masked Study,Double-Blind Methods,Double-Blind Studies,Double-Masked Methods,Double-Masked Studies,Method, Double-Blind,Method, Double-Masked,Methods, Double-Blind,Methods, Double-Masked,Studies, Double-Blind,Studies, Double-Masked,Study, Double-Blind,Study, Double-Masked
D004562 Electrocardiography Recording of the moment-to-moment electromotive forces of the HEART as projected onto various sites on the body's surface, delineated as a scalar function of time. The recording is monitored by a tracing on slow moving chart paper or by observing it on a cardioscope, which is a CATHODE RAY TUBE DISPLAY. 12-Lead ECG,12-Lead EKG,12-Lead Electrocardiography,Cardiography,ECG,EKG,Electrocardiogram,Electrocardiograph,12 Lead ECG,12 Lead EKG,12 Lead Electrocardiography,12-Lead ECGs,12-Lead EKGs,12-Lead Electrocardiographies,Cardiographies,ECG, 12-Lead,EKG, 12-Lead,Electrocardiograms,Electrocardiographies, 12-Lead,Electrocardiographs,Electrocardiography, 12-Lead
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000293 Adolescent A person 13 to 18 years of age. Adolescence,Youth,Adolescents,Adolescents, Female,Adolescents, Male,Teenagers,Teens,Adolescent, Female,Adolescent, Male,Female Adolescent,Female Adolescents,Male Adolescent,Male Adolescents,Teen,Teenager,Youths
D000328 Adult A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available. Adults
D061067 Antibodies, Monoclonal, Humanized Antibodies from non-human species whose protein sequences have been modified to make them nearly identical with human antibodies. If the constant region and part of the variable region are replaced, they are called humanized. If only the constant region is modified they are called chimeric. INN names for humanized antibodies end in -zumab. Antibodies, Humanized,Humanized Antibodies

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